Benzisoxazole and isoxazolo-pyridine compounds and method of use

ABSTRACT

The present invention comprises a new class of compounds capable of modulating the c-kit protein kinase and, accordingly, useful for treatment of c-kit mediated diseases including, without limitation, autoimmune disease, allergies, mastcytosis, mast cell related tumors and various fibrotic diseases. The compounds have a general Formula I 
                         
wherein R 1-5 , X, Y and Z are defined herein. The invention further comprises pharmaceutical compositions, methods for treatment of c-kit mediated diseases, and intermediates and processes useful for the preparation of compounds of the invention.

This application claims the benefit of U.S. Provisional PatentApplication No. 60/832,306, filed Jul. 20, 2006, which disclosure ishereby incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to heterocyclic compounds andtheir use, including use in pharmaceutical formulations, methods oftreatment, and methods of preparing medicaments.

BACKGROUND OF THE INVENTION

C-kit is a receptor tyrosine kinase expressed on the surface of mastcells, to which stem cell factor (SCF) is a ligand. Aberrant c-kitsignaling is believed to be a mediator of certain autoimmune diseases.Binding of SCF to the c-kit receptor mediates various functions of themast cell. As an important mediator of mast cell function, c-kit isthought to also play a role in pathologies associated with mast cells(MC). C-kit functions through mast cell generation, which plays animportant role in triggering autoimmune diseases. Mast cells are tissueelements derived from a particular subset of hematopoietic stem cellsthat express CD34, c-kit and CD13 antigens (Kirshenbaum et al., Blood94:2333-2342, 1999 and Ishizaka et al, Curr. Opinion Immunol. 5:937-943,1993). Mast cells are characterized by their heterogeneity, not onlyregarding tissue location and structure but also at the functional andhistochemical levels (Aldenberg and Enerback, Histochem. J. 26:587-596,1994; Bradding et al., J. Immunol. 155:297-307, 1995; Irani et al., J.Immunol. 147:247-253, 1991).

Mast cells are thought to participate in the destruction of tissues byreleasing various proteases and mediators categorized into three groups:pre-formed granule associated mediators (histamine, proteoglycans, andneutral proteases), lipid-derived mediators (prostaglandins,thromboxanes, and leucotrienes), and various cytokines, including IL-1,IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNFα, GM-CSF, MIP-1a, MIP-1b, MIP-2and IFNγ. The liberation of these mediators induces and activatesvarious components of immune response involved in autoimmune diseases,and also promotes the tissue destruction process.

Activation of the auto-immune response is postulated to be caused by, orstimulated from, the degranulation of mast cells. Immature MCprogenitors circulate in the blood stream and differentiate in thetissues. These differentiation and proliferation processes areinfluenced by various cytokines. Stem Cell Factor (SCF) and IFNγ are twocytokines which are important in influencing such processes. The SCFreceptor is encoded by the proto-oncogene c-kit, which belongs to thetype III receptor tyrosine kinase subfamily (Boissan and Arock, J.Leukoc. Biol. 67:135-148, 2000), along with PDGF and cFMS. Ligation ofc-kit receptor by SCF induces its dimerization followed by itstransphosphorylation, leading to the recruitment and activation ofvarious intracytoplasmic substrates. IFNγ is another cytokine secretedby mast cells. It has been reported that IFNγ is responsible for majorhistocompatibility complexes associated with autoimmune diseases (Hookset al., New England J. of Med., 301:5-8, 1979). These activatedsubstrates induce multiple intracellular signaling pathways responsiblefor cell proliferation and activation (Boissan and Arock, 2000).

TNF is another cytokine produced by mast cells. More recently, it hasbeen reported that the TNF produced by mast cells is involved in thepathogenesis of auto-antibody mediated vasculitis (Watanabe et al.,Blood 11:3855-3866, 1994). Mast cells were also shown to controlneutrophil recruitment during T-cell mediated delayed-typehypersensitivity reactions through TNF and macrophage inflammatoryprotein 2 (MIP-2). Accordingly, c-kit regulation may be useful invarious types of inflammation including without limitation, rheumatoidarthritis, severe asthma, allergy associated chronic rhinitis, and thelike.

Mast cells have also been implicated in liver allograph rejection(Yammaguchi et al., Hematology 29:133-139, 1999) and in liver fibrosis,where hepatic stallate cells produce the SCF that recruits the mastcells (Gaca et al., J. Hematology 30:850-858, 1999). These observationssuggest that c-kit kinase inhibitors may help prevent organ rejectionand fibrosis. Some possible related c-kit mediated therapeuticindications include idiopathic pulmonary fibrosis (IPF) and scleroderma.Mast cells have also been implicated in the pathology of multiplesclerosis (Secor et al., J. Experimental Medicine 191:813-822, 1999),and ischemia-reperfusion injury (Andoh et al, Clinical & ExperimentalImmunology 116:90-93, 1999) in experimental models using mice withmutant kit receptors that are deficient in mast cells. In both cases,the pathology of the diseases was significantly attenuated relative tomice with normal c-kit and mast cell populations. Thus, the role of mastcells in these diseases suggests that c-kit modulators might be usefultherapeutics.

C-kit signaling is also important for fetal gonadal development, andplays a role in adult fertility (Mauduit et al, Human Rep. Update 5:535-545, 1999). Spermatogenesis is inhibited through a reduction ofc-Kit activity in c-kit signaling through the PI3 kinase pathway(Blume-Jensen et al, Nature Genetics 24:157-162, 2000). C-kit expressionhas been observed to be lower in sub-fertile testes than in normaltesticular tissue (Feng et al, Fertility and Sterility 71:85-89, 1999).C-kit signaling is also important for oogenesis and folliculogenesis(Parrott and Skinner, Endocrinology 140:4262-4271, 1999). These reportssuggest that modulation of c-kit enzymatic activity may be a method toreduce both male and female infertility.

While various groups have published on inhibitors of c-kit kinase,disclosing various chemical compounds, including2-phenylamino-imidazo[4,5-h]isoquinolin-9-ones (Snow, R J et al, J. Med.Chem. 2002, 45, 3394), pyrazolo[3,4-d]pyrimidines (Burchat, A F et al,Bioorganic and Med. Chem. Letters 2002, 12, 1987 and Hanke, J H et al,J. Biol. Chem. 1996, 271, 695), pyrrolo[2,3-d]pyrimidines (Altmann, E etal, Bioorganic and Med. Chem. Letters 2001, 11, 853),anilinoquinazolines (Wang, Y D et al, Bioorganic and Med. Chem. Letters2000, 10, 2477), imidazoquinoxalines (Chen, P. et al, Bioorganic andMed. Chem. Letters 2002, 12, 3153), PCT publication entitled, “Methodsof Modulating C-kit Tyrosine Protein Kinase Function with IndolineCompounds” and PCT publication entitled, “Use of Tyrosine KinaseInhibitors for Treating Autoimmune Diseases”, none of these groupsdescribe the compounds of the present invention, and particularly asmodulators of kinase enzymes such as c-kit, and useful for theregulation of autoimmune disease(s), allergies, asthma, cancer and thelike.

BRIEF DESCRIPTION OF EXEMPLARY EMBODIMENTS OF THE INVENTION

The compounds of the present invention, including stereoisomers,tautomers, solvates, pharmaceutically acceptable salts and derivatives,and prodrugs thereof, are represented by general Formula I:

wherein R¹⁻⁵, X, Y and Z are defined in the Detailed Description sectionhereinbelow.

The compounds of Formula I are capable of modulating the activity ofc-kit protein kinase and, therefore, are capable of regulating variousc-kit related disorders. More specifically, these compounds are usefulin the treatment, including preventative, prophylactic and therapeutictreatment, of c-kit kinase-associated or mediated disorders including,but not limited to, mast cell regulated autoimmune disorders andfibrotic disease. In one embodiment of the invention, the compounds ofFormula I are useful for the treatment of mast cell production, tumorsrelated to mast cell proliferation and mastocytosis, allergic reactionsand c-kit mediated fibrotic and autoimmune disease.

To treat patients for such disorders, another embodiment of theinvention provides a pharmaceutical composition comprising a compound ofFormula I and a pharmaceutically acceptable carrier. Such a compositioncan be administered to the subject, such as a human, for the purpose oftreating the disorder. Other therapeutic agents such as those describedbelow may be employed in combination with the inventive compounds, suchas in a combined composition, administered to the subject.Alternatively, such other therapeutic agent(s) may be administered priorto, simultaneously with, or following the administration of thecompound(s) of the present invention.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way.

DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS OF THE INVENTION

In one embodiment, the present invention provides a compound of FormulaI

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein

X is CR⁶R⁶, C(O), NR⁶, O or S(O)_(p) wherein p is 0, 1, or 2;

Y is N or CR³;

Z is —C(O)NR⁶—, —C(S)NR⁶—, —NR⁶C(O)—, —NR⁶C(S)—, —NR⁶C(O)NR⁶—,—NR⁶C(S)NR⁶—, —NR⁶(COO)—, —OC(O)NR⁶—, —S(O)₂NR⁶—, —NR⁶S(O)₂NR⁶— or—NR⁶S(O)₂—;

R¹ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-5 substituents of R⁹;

R² is H, halo, haloalkyl, NO₂, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, CN,OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH, —S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl,—N—(C₁₋₈alkyl)₂ or —C(O)—C₁₋₈alkyl, wherein the C₁₋₈-alkyl, C₂₋₈-alkenyland C₂₋₈-alkynyl optionally comprising 1-4 heteroatoms selected from N,O and S and optionally substituted with one or more substituents of R⁹;

R³, at each occurrence, is H, halo, haloalkyl, NO₂, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH,—S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or —C(O)—C₁₋₈alkyl,wherein the C₁₋₈-alkyl, C₂₋₈-alkenyl and C₂₋₈-alkynyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents of R⁹;

R⁴ is H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl or CN;

R⁵ is C(O)R⁷, COOR⁷, C(O)NR⁷R⁷, C(O)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl and C₂₋₁₀-alkynyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of R⁸ or R⁹; or

R⁵ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-5 substituents of R⁹;

R⁶, at each occurrence, is H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl or CN;

R⁷ is H, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl orC₄₋₈-cycloalkenyl, each of the C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₃₋₈-cycloalkyl and C₄₋₈-cycloalkenyl optionally comprising 14heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸,OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸,NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹),OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹,NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹ or R⁹;

R⁸ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-3 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-3 substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₈-alkyl,C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl,C₁₋₈alkylamino-, C₁₋₈-dialkylamino-, C₁₋₈-alkoxyl, C₁₋₈-thioalkoxyl or asaturated or partially or fully unsaturated 5-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₈alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl, C₁₋₈-alkylamino-, C₁₋₈-dialkylamino-, C₁₋₈-alkoxyl,C₁₋₈-thioalkoxyl and ring of said ring system is optionally substitutedindependently with 1-3 substituents of halo, haloalkyl, CN, NO₂, NH₂,OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl,

provided that when X is NR⁶, then R⁶ at that occurrence is not H.

In another embodiment, the invention provides compounds wherein X isCR⁶R⁶, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein X isC(O), in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein X isNR⁶, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein X is O,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein X isS(O)_(p) wherein p is 0, 1, or 2, in conjunction with any of the aboveor below embodiments.

In another embodiment, the invention provides compounds wherein Y is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein Y isCR³, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein Z is—C(O)NR⁶—, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein Z is—NR⁶C(O)—, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein Z is—S(O)₂NR⁶— or —NR⁶S(O)₂—, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds wherein Z is—NR⁶C(O)NR⁶—, —NR⁶C(S)NR⁶—, —NR⁶(COO)— or —NR⁶S(O)₂NR⁶—, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R¹ isphenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl,benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl, isoindolyl,indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R¹ isphenyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl, thiophenyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl or isothiazolyl, each of which isoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R² is H,F, Br, Cl, I, CF₃, CH₂CF₃, NO₂, C₁₋₈alkyl, CN, OH, —OCH₃, —OC₂H₅, —OCF₃,NH₂, —NH—C₁₋₆alkyl or —N—(C₁₋₈alkyl)₂, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention provides compounds wherein R² is F,Br, Cl, I, CF₃, CN, OH, —OCH₃, —OCF₃, NH₂, methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine,dimethylamine, ethylamine, diethylamine or propylamine, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R³ is H,C₁₋₈alkyl or CN, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds wherein R³ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁴ is H,C₁₋₈alkyl or CN, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds wherein R⁴ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁵ is apartially or fully saturated or unsaturated 5-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein eachring of said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁵ isphenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl,benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl, isoindolyl,indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁵ isphenyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl, thiophenyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, pyrrolidinyl orpyrazolinyl, each of which is optionally substituted independently with1-5 substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds wherein R⁶, ateach occurrence, is H or C₁₋₈alkyl, in conjunction with any of the aboveor below embodiments.

In another embodiment, the invention provides compounds wherein R⁶ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁹ isphenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl,benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl, isoindolyl,indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted independently with 1-5 substituents, as definedherein.

In another embodiment, the invention provides compounds defined byFormula II

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein

A is N or CH;

Y is N or CR³;

each R^(1′), independently, is NR⁸R⁹, NR⁹R⁹, OR⁸, OR⁹, R⁷ or R⁹ and n is0-3;

R² is H, halo, haloalkyl, NO₂, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, CN,OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH, —S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl,—N—(C₁₋₈alkyl)₂ or —C(O)—C₁₋₈alkyl, wherein the C₁₋₈-alkyl, C₂₋₈-alkenyland C₂₋₈-alkynyl optionally comprising 1-4 heteroatoms selected from N,O and S and optionally substituted with one or more substituents of R⁹;

R³, at each occurrence, is H, halo, haloalkyl, NO₂, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH,—S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or —C(O)—C₁₋₈alkyl,wherein the C₁₋₈-alkyl, C₂₋₈-alkenyl and C₂₋₈-alkynyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents of R⁹;

R⁴ is H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl or CN;

R⁵ is C₁₋₈-alkyl, C₂₋₈-alkenyl or C₂₋₈-alkynyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl and C₂₋₁₀-alkynyl optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with one or moresubstituents of R⁸ or R⁹; or

R⁵ phenyl, naphthyl, 2-pyridyl, 2,6-pyrimidinyl, triazinyl, pyridazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, 2,5-imidazolyl, triazolyl, 2,5-thiazolyl,thiadiazolyl, 2,5-oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl,benzoxazolyl, benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl,isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl or cyclohexyl, each ofwhich is optionally substituted independently with 1-5 substituents ofR⁷ or R⁹;

R⁶, at each occurrence, is H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl or CN;

R⁷ is H, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl orC₄₋₈-cycloalkenyl, each of the C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₃₋₈-cycloalkyl and C₄₋₈-cycloalkenyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸,OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸,NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹),OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹,NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹ or R⁹;

R⁸ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-3 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-3 substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₈-alkyl,C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl,C₁₋₈alkylamino-, C₁₋₈-dialkylamino-, C₁₋₈-alkoxyl, C₁₋₈-thioalkoxyl or asaturated or partially or fully unsaturated 5-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₈alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl, C₁₋₈-alkylamino-, C₁₋₈-dialkylamino-, C₁₋₈-alkoxyl,C₁₋₈-thioalkoxyl and ring of said ring system is optionally substitutedindependently with 1-3 substituents of halo, haloalkyl, CN, NO₂, NH₂,OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the invention provides compounds of Formula IIwherein

A is N;

Y is N or CR³;

each R^(1′), independently, is NR⁸R⁹, NR⁹R⁹, R⁷ or R⁹ and n is 1 or 2;

R² is halo, haloalkyl, NO₂, C₁₋₈alkyl, CN, OH, —O—C₁₋₈alkyl,—O-haloalkyl, SH, —S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl or —N—(C₁₋₈alkyl)₂;

R³, at each occurrence, is H;

R⁴ is H, C₁₋₈alkyl or CN; and

R⁶ is H or C₁₋₈alkyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula IIwherein n is one and R^(1′) is NR⁹R⁹, halo, haloalkyl, CN, NO₂, NH₂, OH,oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine ordiisopropylamine, in conjunction with any of the above or belowembodiments.

In many, further embodiments of compounds related to Formula II, X, Y,R², R³, R⁴, R⁵ and R⁶ are as defined in any of the above embodiments inconjunction with compounds of Formula I hereinabove.

In yet another embodiment, there are provided the compounds of Examples1-31 described herein, or a pharmaceutically acceptable salt thereof.

The compounds of Formulas I or II, and stereoisomers, solvates,tautomers, pharmaceutically acceptable salts and derivatives, andprodrugs of these compounds, are useful for treating subjects, typicallymammals such as humans, with various conditions and/or disease states,as previously described. To this end, and in another embodiment, theinvention provides pharmaceutical compositions (also commonly referredto as medicaments, which may be used to treat various conditions ordiseases) comprising one or more of the compounds of Formula I or II,including compounds according to any of the various embodimentsdescribed above, and a pharmaceutically acceptable carrier or diluent.

The compounds of Formula I or II, or pharmaceutical compositioncomprising such compound(s), may be administered in an effective amountto the subject to modulate one or more target proteins in the subjectthereby treating the target-mediated disease or condition. Accordingly,another embodiment of the invention relates to a method for treating ac-kit kinase-mediated disorder in a mammal, comprising administering tothe mammal a therapeutically effective amount of a compound according toany one of the above embodiments.

Further embodiments of the present invention include methods fortreating conditions, disorders or diseases related to c-kit, includingwithout limitation, treating the over-production of histamine in asubject, treating an autoimmune disease, mastocytosis, mast cell tumors,asthma, severe asthma, chronic rhinitis, allergy associated chrinicrhinitis, small cell lung cancer, acute myelocytic leukemia, acutelymphocytic leukemia, myelodysplastic syndrome, chronic myelogenusleukemia, colorectal carcinoma, gastric carcinoma, gastrointestinalstromal tumor, testicular cancer, glioblstoma, astrocytoma, fibroticdiseases including without limitation, idiopathic pulmonary fibrosis, ora combination thereof in a subject, wherein each of the above methods,independently, comprise administering to the subject or mammal atherapeutically effective amount, or a therapeutically effective dosageamount, of a compound according to any one of the above embodimentsrelated to Formulas I or II.

Various other embodiments of the invention relate to the manufactureand/or use of a medicament, comprising a compound of Formulas I or II,for the purposes of treating the subject therewith, as described herein.For example, and in another embodiment, the invention relates to themanufacture of, or use of, a medicament comprising a compound accordingto any one of the above embodiments related to Formulas I or II for thetreatment of fibrotic disease.

Another embodiment of the invention relates to a method of making acompound according to Formula I or II, as described herein, comprisingthe step of reacting a compound 8 having the general formula

wherein R², R³, R⁵ and Y are as defined herein Claim 1 with a compoundhaving a general formula NHR¹R⁶, wherein R¹ and R⁶ are defined herein,in the presence of a carboxylic acid activating agent, to make acompound of Formula I or II.

Meanings and Definitions

Unless otherwise specified, the following terms found in thespecification and claims have the following meanings and/or definitions:

-   -   aq: Aqueous    -   ATP: Adenosine triphosphate    -   BSA: Bovine Serum Albumin    -   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCE: Dichloroethane    -   DCM: Dichloromethane    -   DIEA: Diisopropylethylamine    -   DMF: N,N-Dimethylformamide    -   DMSO: Dimethylsulfoxide    -   DTT: Dithiothreitol    -   EDTA: Ethylene diamine tetraacetic acid    -   EtOAc: Ethyl acetate    -   EtOH: Ethanol    -   FCS: Fetal Calf Serum    -   g: Gram(s)    -   h, hr: Hour(s)    -   HBTU: O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   Hepes: N-[2-Hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]    -   IC₅₀ value: The concentration of an inhibitor that causes a 50%        reduction in a measured activity.    -   IPA isopropyl alcohol    -   LiHMDS: Lithium bis(trimethylsilyl)amide    -   MeI: Methyl iodide    -   MeCN: Acetonitrile    -   MeOH: Methanol    -   min: Minute(s)    -   mmol: Millimole(s)    -   NCS: N-chlorosuccinimide    -   NMP: N-methylpyrrolidone    -   RT: Room temperature    -   TFA: Trifluoroacetic acid    -   THF: Tetrahydrofuran

Generally, reference to a certain element such as hydrogen or H is meantto include all isotopes of that element. For example, if an R group isdefined to include hydrogen or H, it may also include deuterium andtritium. Compounds comprising radioisotopes such as tritium, C¹⁴, P³²and S³⁵ are thus within the scope of the invention. Procedures forinserting such labels into the compounds of the invention will bereadily apparent to those skilled in the art based on the disclosureherein.

The term “substituted” as used herein refers to a group, such as thosedefined below, in which one or more bonds to a hydrogen atom containedtherein are replaced by a bond to non-hydrogen or non-carbon atomsincluding, but not limited to, a halogen atom such as F, Cl, Br, and I;an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxygroups, and ester groups; a sulfur atom in groups such as thiol groups,alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, andsulfonyl groups such as sulfonyl halides and sulfonomides; a nitrogenatom in groups such as amines, amides, alkylamines, dialkylamines,arylamines, alkylarylamines, diarylamines, N-oxides, ureas, imines,imides, and enamines; a silicon atom in groups such as in trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.Substituted alkyl groups and also substituted cycloalkyl groups andothers also include groups in which one or more bonds to a carbon(s) orhydrogen(s) atom is replaced by a bond to a heteroatom such as oxygen incarboxylic acid, ester and carbamate groups; and nitrogen in groups suchas imines, oximes, hydrazones, and nitriles.

Substituents, including alkyl and ring groups, may be either monovalentor polyvalent depending on the context of their usage. For example, ifdescription contained the group R¹-R²-R³ and R² was defined asC₁₋₆alkyl, then the R² alkyl would be considered polyvalent because itmust be bonded to at least R¹ and R³. Alternatively, if R¹ were definedas C₁₋₆alkyl, then the R¹ alkyl would be monovalent (excepting anyfurther substitution language).

The term “unsubstituted” as used herein with reference to a group, meansthat the group does not have one or more bonds to a hydrogen or carbonatom contained therein replaced by a bond to non-hydrogen or non-carbonatom, as described above.

The term “optionally substituted” as used herein with reference to agroup, means that the group may be substituted with a specified numberof defined substituents or the group may remain unsubstituted.Generally, the scope of the contemplated substitutions of a particulargroup will be specified.

The term “alkyl” as used herein either alone or within other terms suchas “haloalkyl”, “alkylamino” and “cycloalkyl”, refers to linear,branched or cyclic radicals having one to about twelve carbon atoms.“Cycloalkyl” is also used exclusively herein to refer specifically tofully or partially saturated cyclic alkyl radicals. Examples of “alkyl”radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, cyclopropyl, cyclopentyl,cyclohexyl and the like.

The term C_(a-b)alkyl” as used herein refers to an alkyl groupcomprising from a to b carbon atoms in a branched, cyclical or linearrelationship or any combination of the three. The alkyl groups describedin this section may also contain double or triple bonds. Examples ofC₁₋₈alkyl include, but are not limited to the following:

The term “halogen” and “halo” as used herein, refers to a halogen atomsselected from F, Cl, Br and I.

The term “haloalkyl”, as used herein refers to radicals wherein any oneor more of the alkyl carbon atoms is substituted with halo as definedabove. Specifically embraced are monohaloalkyl, dihaloalkyl andpolyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl radical,for one example, may have an iodo, bromo, chloro or fluoro atom withinthe radical. Dihalo and polyhaloalkyl radicals may have two or more ofthe same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. The term “perfluoroalkyl” means alkyl radicals havingall hydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

The term “C_(a-b)haloalkyl” as used herein refers to an alkyl group, asdescribed above, wherein any number, and at least one, of the hydrogenatoms attached to the alkyl chain are replaced by F, Cl, Br or I.Examples of haloalkyl includes, without limitation, trifluoromethyl,pentafluoroethyl and the like.

The term “hydroxyalkyl” as used herein refers to linear or branchedalkyl radicals having one to about ten carbon atoms any one of which maybe substituted with one or more hydroxyl radicals. Examples of suchradicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl and hydroxyhexyl.

The term “alkoxy” as used herein refers to linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. Alkoxy radicals may be furthersubstituted with one or more halo atoms, such as fluoro, chloro orbromo, to provide “haloalkoxy” radicals. Examples of lower haloalkoxyradicals having one to three carbon atoms include fluoromethoxy,chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy andfluoropropoxy.

The term “sulfonyl”, as used herein whether alone or linked to otherterms such as alkylsulfonyl, refers respectively to divalent radicals—SO₂—.

The term “amino”, as used herein whether alone or linked to other terms,refers to a nitrogen radical containing two hydrogen atoms (NH₂), anitrogen radical which is mono-substituted such as an alkylamine(methylamine for example), or a nitrogen radical which is disubstitutedsuch as a dialkylamine (dimethylamine for example). Generally, the aminenitrogen is the point of attachment to the group in question.Accordingly, the term “alkylamino” or dialkylamino” as used herein,means a mono-alkyl or bis-alkyl substituted amine-linked group. The term“cycloalkylamino” refers to an amine-linked cycloalkyl group. The term“arylamino” refers to an amine-linked aryl group. The term“heteroarylamino” refers to an amine-linked heteroaryl group. The term“heterocyclylamino” refers to an amino-linked heterocyclyl group.

The phrase “partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S″ asused herein, means each ring of the single, double or triple ringradical or ring system (fused ring radical in the case of a double ortriple) may be a carbocyclic ring (“cycloalkyl”), an aromatic carbocycle(an “aryl” group), a heterocyclic ring or a heteroaromatic ring (a“heteroaryl” ring), each of which is optionally substituted asspecified.

The term “aryl”, as used herein alone or in combination, refers to acarbocyclic aromatic system containing one, two or three rings whereinsuch rings may be attached together in a fused manner. The term “aryl”includes, without limitation, aromatic radicals such as phenyl,naphthyl, indenyl, tetrahydronaphthyl, and indanyl. The “aryl” group mayhave 1 to 3 substituents such as alkyl, hydroxyl, halo, haloalkyl,nitro, cyano, alkoxy and alkylamino. “Aryl” also includes the moietywherein the aromatic carbocycle is fused with a C₃₋₆cycloalkyl bridge,wherein the bridge optionally includes 1, 2 or 3 heteroatoms selectedfrom N, O and S. For example, phenyl substituted with —O—CH₂—O— formsthe aryl benzodioxolyl substituent.

The term “heterocyclic” as used herein, refers to fully or partiallysaturated heteroatom-containing ring radicals, where the heteroatom(s)may be selected from nitrogen, sulfur and oxygen.

The term “heterocycloalkyl” as used herein, refers to saturated andpartially saturated (or partially unsaturated) heteroatom-containingring radicals, where the heteroatoms may be selected from nitrogen,sulfur and oxygen. It does not include rings containing —O—O—, —O—S— or—S—S— portions. Said “heterocycloalkyl” group may have 1 to 3substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl,oxo, alkoxy, amino and alkylamino.

Examples of saturated heterocycloalkyl radicals include saturated 3 to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

The term “heteroaryl” as used herein, refers fully unsaturatedheteroatom-containing ring radicals, where the heteroatoms may beselected from nitrogen, sulfur and oxygen. Examples of heteroarylradicals, include unsaturated 5 to 6 membered heteromonocyclyl groupcontaining 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groupcontaining an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl];unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

The term “heteroaryl” also embraces radicals where heterocyclic radicalsare fused/condensed with aryl radicals (also referred to herein as“arylheterocycloalkyl”): unsaturated condensed heterocyclic groupcontaining 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Preferredheterocyclic radicals include five to ten membered fused or unfusedradicals. More preferred examples of heteroaryl radicals includequinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl,oxazolyl, furyl, and pyrazinyl. Other preferred heteroaryl radicals are5- or 6-membered heteroaryl, containing one or two heteroatoms selectedfrom sulfur, nitrogen and oxygen, selected from thienyl, furyl,pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.

Further examples of suitable heterocycles and heteroaryls, some of whichhave been described above, include, without limitation, the following:

“Saturated or unsaturated” means a moiety or substituent that iscompletely saturated, completely unsaturated, or has any degree ofunsaturation therein. Examples of a saturated or unsaturated 6-memberedring carbocycle would include phenyl, cyclohexyl, cyclohexenyl andcyclohexadienyl.

The term “salt” refers to a salt form of a free base compound of thepresent invention, as appreciated by persons of ordinary skill in theart. Salts may be prepared by conventional means, known to those skilledin the art. The term “pharmaceutically-acceptable”, when used inreference to a salt, refers to salt forms of a given compound, which arewithin governmental regulatory safety guidelines for ingestion and/oradministration to a subject. The term “pharmaceutically-acceptablesalts” embraces salts commonly used to form alkali metal salts and toform addition salts of free acids or free bases. The nature of the saltis not critical, provided that it is safe and consideredpharmaceutically-acceptable.

Suitable pharmaceutically-acceptable acid addition salts of compounds ofFormulas I-II may be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, example of which are formic, acetic, adipic, butyric, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid.

Suitable pharmaceutically-acceptable base addition salts of compounds ofFormulas I-II include metallic salts, such as salts made from aluminum,calcium, lithium, magnesium, potassium, sodium and zinc, or salts madefrom organic bases including primary, secondary and tertiary amines,substituted amines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, trimethylamine.

Additional examples of such acid and base addition salts can be found inBerge et al., J. Pharm. Sci., 66, 1 (1977). All of these salts may beprepared by conventional means from the corresponding compound of theinvention by reacting, for example, the appropriate acid or base withthe compound of Formulas I-II.

Also, the basic nitrogen-containing groups of compounds of Formulas I-IIcan be quaternized with such agents as lower alkyl halides including,without limitation, methyl, ethyl, propyl, and butyl chloride, bromidesand iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl, anddiamyl sulfates, long chain halides such as decyl, lauryl, myristyl andstearyl chlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides, and others. Water or oil-soluble or dispersibleproducts may be obtained by quaternizing such basic nitrogen groups incompounds of Formulas I-II.

The term “derivative” as used herein, refers to simple modifications,readily apparent to those of ordinary skill in the art, on the parentcore structure of Formulas I or II, which does not significantly affect(generally decrease) the activity of the compound in-vitro as well as invivo, in a subject. The term, “derivative” as used herein, iscontemplated to include pharmaceutically acceptable derivatives ofcompounds of Formulas I or II.

The term “pharmaceutically acceptable” when used with reference to aderivative, is consistent in meaning with reference to a salt, andrefers to a derivative that is pharmacologically safe for consumption,generally as determined by a governmental or authorized regulatory body.

The term “leaving group” as used herein, refers to groups readilydisplaceable by a nucleophile, such as an amine, a thiol or an alcoholnucleophile. Leaving groups are well known in the art. Examples ofleaving groups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

The term “protecting group” as used herein, refers to groups well knownin the art which are used to prevent selected reactive groups, such ascarboxy, amino, hydroxy, mercapto and the like, from undergoingundesired reactions, such as nucleophilic, electrophilic, oxidation,reduction and the like. Preferred protecting groups are indicated hereinwhere appropriate. Examples of amino protecting groups include, but arenot limited to, aralkyl (also known as arylalkyl), substituted aralkyl,cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substitutedallyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like.Examples of aralkyl include, but are not limited to, benzyl,ortho-methylbenzyl, trityl and benzhydryl, which can be optionallysubstituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyland the like, and salts, such as phosphonium and ammonium salts.Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl,9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples ofcycloalkenylalkyl or substituted cycloalkylenylalkyl radicals,preferably have 6-10 carbon atoms, include, but are not limited to,cyclohexenyl methyl and the like. Suitable acyl, alkoxycarbonyl andaralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl,iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl,tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixtureof protecting groups can be used to protect the same amino group, suchas a primary amino group can be protected by both an aralkyl group andan aralkoxycarbonyl group. Amino protecting groups can also form aheterocyclic ring with the nitrogen to which they are attached, forexample, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl,maleimidyl and the like and where these heterocyclic groups can furtherinclude adjoining aryl and cycloalkyl rings. In addition, theheterocyclic groups can be mono-, di- or tri-substituted, such asnitrophthalimidyl. Amino groups may also be protected against undesiredreactions, such as oxidation, through the formation of an addition salt,such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid andthe like. Many of the amino protecting groups, including aralkyl groupsfor example, are also suitable for protecting carboxy, hydroxy andmercapto groups. Alkyl groups are also suitable groups for protectinghydroxy and mercapto groups, such as tert-butyl.

Silyl protecting groups are groups containing silicon atoms which areoptionally substituted by one or more alkyl, aryl and aralkyl groups.Suitable silyl protecting groups include, but are not limited to,trimethylsilyl, triethylsilyl, tri-isopropylsilyl,tert-butyldimethylsilyl, dimethylphenylsilyi,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-tri-silyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′═O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. The term “prodrug”, as used herein, refers to acompound, which when administered to the body of a subject (such as amammal), breaks down in the subject's metabolic pathway to provide anactive compound of Formulas I or II. More specifically, a prodrug is anactive or inactive “masked” compound that is modified chemically throughin vivo physiological action, such as hydrolysis, metabolism and thelike, into a compound of this invention following administration of theprodrug to a subject or patient. The suitability and techniques involvedin making and using prodrugs are well known by those skilled in the art.For a general discussion of prodrugs involving esters see Svensson andTunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design ofProdrugs, Elsevier (1985).

One common form of a prodrug is a masked carboxylic acid group. Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bundgaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as phosphates, estersand ethers. EP 039,051 (Sloan and Little, Apr. 11, 1981) disclosesMannich-base hydroxamic acid prodrugs, their preparation and use.

Stereoisomers of the compounds of the present invention are alsocontemplated herein. The term “stereoisomer” as used herein refers to acompound having one or more asymmetric centers. Chiral centers in acompound generally cause that compound to exist in many differentconformations or stereoisomers. The term “stereoisomers” includesenantiomers, diastereomers, atropisomers and geometric isomers.Stereoisomers generally possess different chemical properties and/orbiological activity, as appreciated by those skilled in the art. Forexample, one stereoisomer may be more active and/or may exhibitbeneficial effects in comparison to other stereoisomer(s) or whenseparated from the other stereoisomer(s). However, it is well within theskill of the ordinary artisan to separate, and/or to selectively preparesaid stereoisomers. Accordingly, “stereoisomers” of the presentinvention necessarily include mixtures of stereoisomers, includingracemic mixtures, individual stereoisomers, and optically active forms.

The term “solvate” when used with reference to a compound refers to acompound, which is associated with one or more molecules of a solvent,such as an organic solvent, inorganic solvent, aqueous solvent ormixtures thereof. The compounds of Formulas I or II may also besolvated, especially hydrated. Hydration may occur during manufacturingof the compounds or compositions comprising the compounds, or thehydration may occur over time due to the hygroscopic nature of thecompounds. Compounds of the invention may exist as organic solvates aswell, including DMF, ether, and alcohol solvates among others. Theidentification and preparation of any particular solvate is within theskill of the ordinary artisan of synthetic organic or medicinalchemistry.

The term “treatment” as used herein, includes therapeutic treatment aswell as prophylactic treatment (either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals).

The term “therapeutically-effective” as used herein, is intended toqualify the amount of each compound of Formulas I or II, which willachieve the goal of treatment, for example, improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies.

The term “C-kit-mediated disease or disease states” refer to all diseasestates wherein C-kit plays a role, either directly as C-kit itself, orby C-kit inducing or mediating other proteins, cytokines, enzymes ordisease-causing agents and the like to be released, activated orotherwise directly or indirectly regulated.

The specification and claims contain a listing of species using thelanguage “selected from . . . and . . . ” and “is . . . or . . . ”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups from the genus.

Synthesis

Compounds of Formula I and II can be synthesized according to one ormore of the following schematic procedures and specific methods whereinthe substituents are as defined for Formulas I and II, above, exceptwhere further noted. The procedures and methods as shown relate topreparation of compounds having unspecified stereochemistry. However,such procedures and methods may generally be applied to those compoundsof a specific stereochemistry, e.g., where the stereochemistry about agroup is (S) or (R).

In addition, the compounds having one stereochemistry (e.g., (R)) canoften be utilized to produce those having opposite stereochemistry(i.e., (S)) using well-known methods, for example, by inversion.

Compounds and examples taught herein are either named with conventionalIUPAC naming system or with the naming system utilized in ChemDraw,software version 8.0.

Scheme 1 describes a general method for preparingamino-carboxylate-substituted benzisoxazole compounds 7, of Formulas Iand II (wherein part of “Z” is a carbonyl). As shown, a desirablysubstituted fluoro-benzene (or pyridine) 1 can be treated with a strongbase, such as n-butyllithium, and methylchloroformate, under suitableconditions, to provide the corresponding carboxylate intermediate 2.Formylation of compound 2 may be accomplished using a suitable base,such as LDA, in the presence of DMF, to generate compound 3. Thealdehyde of compound 3 can be converted to the corresponding oxime,using hydroxylamine, as shown in a suitable solvent, as shown above, toprovide compound 4. Intermediate 4 can be treated with a suitablechlorinating agent, such as N-chlorosuccinimide (NCS), to install aleaving group (LG) chlorine adjacent the oxime, as in compound 5.Compound 5 may be reacted with a desirably substituted amine undersuitable conditions, to provide the corresponding amino oxime 6. Oxime 6can be reacted with a strong base, such as NaH, in the presence of DMFto afford the benzisoxazole intermediate 7.

Similarly, a benzopyrazole compound (not shown, where X in Formulas Iand II is N) can be made by conventional methods, known in the art. Forexample, such cores may be made by methods described in J. Med. Chem.26, pg 1307., 1983, which is incorporated herein by reference in itsentirety. In that reference, the aldehyde of compound 3 may be a ketone,which can then be reacted with a hydrazine, or substituted hydrazine, toafford the corresponding N—H or N-methyl adduct. This adduct may becyclized via an intramolecular cyclization reaction, in a manner similarto that of the oxime in scheme 1, to provide the desired benzopyrazolecompound intermediate (not shown), which may be used to make desirablysubstituted benzopyrazole compounds of Formulas I and II.

3-Amino-3-amido-1,2-benzisoxazole compounds 9, of formulas I and II, canbe made by the general method described in Scheme 2. As shown, anamino-carboxylate-substituted benzisoxazole compound 7, can behydrolyzed with a suitable base, such as LiOH, in a suitable solvent toprovide the corresponding carboxylic acid intermediate 8. Activation ofthe acid 8 with a suitable coupling reagent, which is discussed in moredetail below and which are well known in the art, followed by treatmentof the activated acid (not shown) with a suitable and desired amino R¹group using conventional coupling conditions, to generate compound 9. Inthis manner, analogue compounds 9 having an amide Z linker may be madesimply be varying the amine reagents used to couple the acidintermediate 8.

Amines, carbamates, esters, ureas and the like linker Z groups may bemade by one or more of the methods described in scheme 3 below.

Scheme 3 describes various exemplary coupling methods whereby desiredlinkers “Z” may be made or formed between the benzisoxazole “B” ring anda desired R¹ group or ring “A”, as illustrated in Formulas I and IIherein. It is contemplated herein that the R¹ group need not be a ringdirectly attached to the Z linker group, but may be a linear, non cyclicgroup as described herein. Accordingly, while “A” is shown as a ring, itis not so limited in scheme 3, and also includes non-cyclic groupshaving the designated functional groups, which will participate informing the desired Z linker group.

Each of the seven sub-schemes, numbered 1-7 above and described below,utilize the following meanings for (R)_(n), X, Nu⁻, E⁺, W and m: (R)_(n)refers to n number of R² or R³ substitutions wherein n is an integerfrom 0-3; X refers generally to a “leaving group” such as a halide(bromine, chlorine, iodine or fluorine), alkylsulfonate and other knownleaving groups (also see definitions herein); Nu⁻ refers generally to anucleophile or nucleophilic species such as a primary or secondaryamine, an oxygen, a sulfur or a anionic carbon species—examples ofnucleophiles include, without limitation, amines, hydroxides, alkoxidesand the like; E⁺ refers generally to an electrophile or electrophilicspecies, such as the carbon atom of a carbonyl or carbon atom attachedto an activated leaving group, the carbon atom of which is susceptibleto nucleophilic attack or readily eliminates—examples of suitableelectrophilic carbonyl species include, without limitation, acidhalides, mixed anhydrides, aldehydes, carbamoyl-chlorides, sulfonylchlorides (sulfonyl electrophile), acid carbonyls activated withcarboxylic acid activating reagents such as TBTU, HBTU, HATU, HOBT, BOP,PyBOP, carbodiimides (DCC, EDC and the like), pentafluorophenyl, andother electrophilic species including halides, isocyanates (see ring Areagent of sub-scheme 3), diazonium ions and the like; W is either O orS; and m is either 0 or 1.

The coupling of groups B and A, as shown as products in sub-schemes 1-7,can be brought about using various conventional methods to link groups Band A together. For example, an amide or a sulfonamide linker “Z”, asshown in sub-schemes 1 (where m=0), 2, 4, 5, 6 and 7 where the Nu− is anamine, respectively, can be made utilizing an amine on either the B or Agroups and an acid chloride or sulfonyl chloride on the other of eitherthe A or B groups. The reaction proceeds generally in the presence of asuitable solvent and/or base. The reaction proceeds generally in thepresence of a suitable solvent and/or base. Suitable solvents include,without limitation, generally non-nucleophilic, aprotic solvents such astoluene, CH₂Cl₂, THF, DMF, DMSO, N,N-dimethylacetamide and the like, andsolvent combinations thereof. The solvent(s) may range in polarity, asappreciated by those skilled in the art. Suitable bases include, forexample, mild bases such as tertiary amine bases including, withoutlimitation, DIEA, TEA, N-methylmorpholine; and stronger bases such ascarbonate bases including, without limitation, Na₂CO₃, K₂CO₃, Cs₂CO₃;hydrides including, without limitation, NaH, KH, borohydrides,cyanoborohydrides and the like; and alkoxides including, withoutlimitation, NaOCH₃, and the like. The base itself may also serve as asolvent. The reaction may optionally be run neat, i.e., without any baseand/or solvent. For simple structurally unhindered substrates, thesecoupling reactions are generally fast and conversion occurs typically inambient conditions. However, depending upon the particular substrate,steric hindrance, concentration and other stoichiometric factors, suchreactions may be sluggish and may require a basicity adjustment or heat,as appreciated by those skilled in the art.

As another example, a urea linker (or a sulfonylurea linker), as shownin sub-scheme 3, may be made by reacting an amine with a desiredisocyanate. As isocyanates are generally highly reactive species, theurea formation generally proceeds quickly, at ambient temperatures witha minimal amount of solvent, as appreciated by those of ordinary skillin the art. The reaction may optionally be run neat, i.e., without anybase and/or solvent.

Similarly, carbamate Z linkers are illustrated in sub-scheme 1 (wherem=1) where Nu− would be an amine, anhydride linkers are illustrated insub-scheme 1 where Nu− would be an oxygen, reverse amide linkers aregenerally illustrated in sub-scheme 6 where Nu− would be an amine and E+would be an acid chloride, urea linkers are illustrated in sub-scheme 3,thioamide and thiourea linkers are illustrated in sub-schemes 2 and 3where the respective carbonyl oxygen is a sulfur, and thiocarbamates areillustrated in sub-schemes 1 where the respective carbonyl oxygen and/orcarbamate oxygen is a sulfur. While the above methods are so described,they are not exhaustive, and other methods for linking groups A and Btogether may be utilized as appreciated by those skilled in the art.

Although sub-schemes 1-7 are illustrated as having the nucleophilic andelectrophilic coupling groups, such as the amino group and acid chloridegroups illustrated in sub-scheme 2, directly attached to the substrate,either the A or B group, in question, the invention is not so limited.It is contemplated herein that these nucleophilic and/or electrophiliccoupling groups may be tethered from their respective group. Forexample, the amine group on the B group, and/or the acid halide group onthe A group, as illustrated in sub-scheme 2, may be removed from directattachment to the group by a one or more atom spacer, such as by amethylene, ethylene, propylene spacer or the like. As appreciated bythose skilled in the art, such spacer may or may not affect the couplingreactions described above, and accordingly, such reaction conditions mayneed to be modified to affect the desired transformation.

The coupling methods described in sub-schemes 1-7 of scheme 3 are alsoapplicable for coupling desired A groups to desired R⁵—N(R⁴)—B groupintermediates (sub-schemes 1-4), to synthesize desired compounds ofFormulas I and II. For example, an amine-protected B ring intermediatemay be first coupled to a desired R⁴R⁵N— group, as illustrated inFormulas I and II, to form the R⁵—N(R⁴)—B intermediate. The protectedamine may then be de-protected and used to form an amide linker, orconverted to an isocyanate, for example, or any other desired group forcoupling the A ring via the desired linker. Suitable B ring aminoprotecting groups include t-butoxycarbonyl group, which can be made withBOC-ON, exist as appreciated by those skilled in the art and furtherdescribed herein.

The Specific Methods and Examples described in detail below furtherexemplify the synthesis of compounds of Formulas I and II, generallydescribed in Schemes 1 and 2 above.

Analytical Methods:

LC-MS Methods:

Unless otherwise noted, the LC-MS analysis of exemplary compounds,intermediates and starting materials described herein were conductedusing one or both of the following two methods:

Method A:

Samples were generally run on an Agilent-1100 system with a PhenomenexLuna C₈ (5μ) reverse phase column (4.6×100 mm) run at 40° C. with a flowrate of 1.0 mL/min. The mobile phase used solvent A (H₂O/0.1% TFA) andsolvent B (CH₃CN/0.1% TFA) with a 7 min gradient from 10% to 100% CH₃CN,and a 2.5 min hold at 100% CH₃CN. The gradient was followed by a 1 minreturn to 10% CH₃CN and a 2 min flush.

Method B:

Samples were run on an Agilent 1100 system with a Phenomenex-Synergy MAX(4μ) reverse phase column (2.0×50 mm) run at 40° C. with a flow rate of0.8 mL/min. The mobile phase used solvent A (H₂O/0.1% TFA) and solvent B(CH₃CN/0.1% TFA) with a 3 min gradient from 10% to 100% CH₃CN. Thegradient was followed by a 0.5 min return to 10% CH₃CN and a 1.5 minflush.

Alternatively, samples may be purified using an HP-1000 or HP-1050system with an HP Zorbax SB-C₁₈ (5μ) reverse phase column (4.6×150 mm)run at 30° C. with a flow rate of 1.00 mL/min. The mobile phase may usesolvent A (H₂O/0.1% TFA) and solvent B (CH₃CN/0.1% TFA) with a 20 mingradient from 10% to 90% CH₃CN. The gradient may be followed by a 2 minreturn to 10% CH₃CN and a 3 min flush.

EXAMPLE 1

Synthesis of6-chloro-3-(4-ethylphenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamideStep 1: Methyl 2-chloro-6-fluorobenzoate

An oven-dried round bottom flask successively evacuated and purged withN₂ gas was charged with drisolv THF (84 ml) and placed in a −78° C. dryice/acetone bath. To this was added n-butyllithium (2.5 M in hexanes)(18 ml, 46 mmol) and the mixture was stirred for 10 min before addingneat 1-chloro-3-fluorobenzene (5.48 g, 42.0 mmol). The solution wasstirred for 2 hrs before adding neat methyl chloroformate (4.0 ml, 50mmol). The resultant solution was stirred at −78° C. for 3 hrs and thenallowed to warm to RT. Water was added to the mixture followed by EtOAc.The layers were separated and the aqueous layer was extracted 3× EtOAc.The combined organics were washed with brine, dried over MgSO4, filteredand concentrated to give the title compound as a clear liquid.

Step 2: Methyl 6-chloro-2-fluoro-3-formylbenzoate

An oven-dried round bottom flask successively evacuated and purged withN₂ gas was charged with drisolv THF (13.3 ml), and diisopropyl amine(6.6 ml, 46 mmol). The mixture was placed in a −78° C. dry ice/acetonebath before n-butyllithium (2.5 M in hexanes) (17 ml, 43 mmol) wasadded. The LDA solution was then placed in a 0° C. bath for 10 minutes,then recooling to −78° C. A solution of methyl 2-chloro-6-fluorobenzoate(3.50 g, 19 mmol) in THF (56 ml) was added to the mixture dropwise over30 minutes. The resulting mixture was stirred at −78° C. for 2.5 hrs,warmed to −50° C. over 30 min, and stirred for 30 minutes at −50° C. Themixture was then recooled to −78° C. and drisolv dimethylformamide (14ml, 186 mmol) was added. The resulting mixture was stirred for 30minutes at −78° C. and then gradually warmed to RT over 1 h (note: donot stir very long after reaching RT). The reaction was quenched with10% aqueous acetic acid, diluted with EtOAc and the layers wereseparated. The aqueous layer was extracted three times with EtOAc. Thecombined organic layers were washed with water, brine, and dried overNa₂SO₄, filtered and concentrated to a yellow oil, which was purified bysilica gel chromatography using 12:1 hexanes/ethyl acetate to give thetitle compound as a light yellow oil, which solidified upon evacuation.

Step 3: Methyl-6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate

To a solution of methyl-6-chloro-2-fluoro-3-formylbenzoate (930 mg, 4294μmol) in ethanol (14.5 ml) at RT was added hydroxylamine (50 wt. %aqueous solution) (1316 μl, 21469 μmol) and the solution was stirred for16 hrs. The volatiles were removed under reduced pressure, and theresidue was diluted with water, which caused a solid to precipitate. Thesolid was collected by filtration and washed with water and dried invacuo to give an off-white solid.

Step 4: methyl-6-chloro-3-(chloro(hydroxyimino)methyl)-2-fluorobenzoate

To a solution ofmethyl-6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (553 mg, 2388μmol) in DMF (5.3 ml) at 0° C. was added N-chlorosuccinimide (351 mg,2626 μmol). The mixture was heated to 50° C. for 10 min after which timeLCMS analysis indicated the reaction was complete. The mixture wascooled to RT, water was added followed by EtOAc, the layers wereseparated, and the aqueous was extracted with EtOAc (3×). The combinedorganic layers were washed with brine (2×), dried over MgSO₄, filteredand concentrated to yield the title compound as a yellow viscous oil,which solidified under reduced pressure.

Step 5:methyl-6-chloro-3-(N-(4-ethylphenyl)-N′-hydroxycarbamimidoyl)-2-fluorobenzoate

4-Ethylaniline (923 μl, 7423 μmol) was added dropwise to a 0° C. chilledsolution ofmethyl-6-chloro-3-(chloro(hydroxyimino)methyl)-2-fluorobenzoate (395 mg,1485 μmol) in anhydrous THF (4.5 ml). The resultant mixture was stirredfor one hour before the ice bath was removed and the mixture was allowedto warm to RT. After stirring for several hours at RT, LCMS analysisindicated the reaction was complete. The solvent was removed solvent invacuo and the brown residue was diluted with brine and EtOAc. The layerswere separated and the aqueous was extracted with EtOAc (3×). Thecombined organics were dried over MgSO₄, filtered and concentrated to abrown oil which was purified by silica gel chromatography using 2:1Hex/EtOAc to afford the desired product.

Step 6:Methyl-6-chloro-3-(4-ethylphenylamino)benzo[d]isoxazole-7-carboxylate

To a solution ofmethyl-6-chloro-3-(N-(4-ethylphenyl)-N′-hydroxycarbamimidoyl)-2-fluorobenzoate(225 mg, 641 μmol) in DMF (6.4 ml) chilled to 0° C. was added NaH (17mg, 706 μmol) in one portion. The yellow solution evolved gas andimmediately turned a dark orange color. After 20 min, the mixture wasdiluted with H₂O and DCM, the layers were separated and the aqueouslayer was extracted with DCM (2×). The organic layers were combined andwashed with brine, dried over MgSO₄, filtered and concentrated toprovide the title compound as a light brown solid, which was used forthe next step without further purification.

Step 7: 6-Chloro-3-(4-ethylphenylamino)benzo[d]isoxazole-7-carboxylicacid

To a solution ofmethyl-6-chloro-3-(4-ethylphenylamino)benzo[d]isoxazole-7-carboxylate(211 mg, 638 μmol) in dioxane (10.5 ml) was added a 1N aqueous solutionof LiOH hydrate (134 mg, 3190 μmol) and the resulting mixture was heatedto 50° C. After 1 hr, the solvent was removed in vacuo, the residue wasdiluted with H₂O and acidified to pH2 with 2N HCl. After diluting withEtOAc, the layers were separated and the aqueous layer was extractedwith EtOAc (3×). The organics were combined, washed with brine, driedover MgSO₄, filtered and concentrated to obtain the title compound as abrown solid, which was used without further purification.

Step 8:6-Chloro-3-(4-ethylphenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide

6-Chloro-3-(4-ethylphenylamino)benzo[d]isoxazole-7-carboxylic acid(0.195 g, 0.615 mmol) was dissolved in DMF, followed by TEA (0.223 ml,1.61 mmol) and HATU (0.285 g, 0.749 mmol). The mixture was allowed tostir for 5 min before adding pyrimidin-5-amine (0.0509 g, 0.535 mmol)and the mixture was heated to 50° C. overnight. The mixture was thencooled to RT, partitioned between EtOAc/brine, the layers wereseparated, and the aqueous was extracted with EtOAc (3×). The combinedorganics were washed with H₂O and brine, filtered and concentrated. Thecrude material was purified by silica gel chromatography using 20:1DCM/MeOH to give6-Chloro-3-(4-ethylphenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamideas a light brown solid. MS calculated 393.8, found M+H⁺=394.1.

EXAMPLE 2

Synthesis ofN-(2-acetamidopyrimidin-5-yl)-6-chloro-3-(3-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxamideStep A: N-(5-nitropyrimidin-2-yl)acetamide

To 2-amino-5-nitropyrimidine (0.42 g, 3.0 mmol) dissolved in toluene (2ml) was added acetic anhydride (1.4 ml, 15 mmol). The reaction mixturewas stirred at 90° C. for 15 hr, after which an additional amount ofacetic anhydride was added (0.7 mL) and the mixture was stirred atreflux for another 16 h. The solvent was removed in vacuo and to theresidue was added hexane (10 mL) and DCM (1 mL). The solid was collectedby filtration, dried to give N-(5-nitropyrimidin-2-yl)acetamide as anoff-white solid. MS (ESI, pos. ion) m/z: 183 (M+1).

Step B: N-(5-aminopyrimidin-2-yl)acetamide

To N-(5-nitropyrimidin-2-yl)acetamide (0.54 g, 3.0 mmol) suspended inEtOH (20 mL) under N₂ was added palladium, 10 wt. % on activated carbon(0.32 g, 0.3 mmol). The reaction mixture was hydrogenated under 1 atm ofH₂ at RT for 2 h and then filtered through a pad of celite and washedwith MeOH. The filtrate was concentrated to giveN-(5-aminopyrimidin-2-yl)acetamide as a light-yellow solid. MS (ESI,pos. ion) m/z: 153 (M+1).

Step C:N-(2-acetamidopyrimidin-5-yl)-6-chloro-3-(3-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxamide

A round-bottomed flask was charged with6-chloro-3-(3-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxylicacid (0.1 g, 0.28 mmol, made by the method described in Example 1),n,n-diisopropylethylamine (0.07 mL, 0.42 mmol),o-(7-azabenzotriazol-1-yl)-n,n,n′,n-tetramethyluroniumhexafluorophosphate (0.15 g, 0.39 mmol), and DMF (1 mL). This mixturewas stirred for 15 min before N-(5-aminopyrimidin-2-yl)acetamide (0.045g, 0.29 mmol, Step B) was introduced. The reaction mixture was stirredat 60° C. for 16 h, then partitioned between EtOAc (15 ml) and brine (10mL). The aqueous layer was back exacted with EtOAc (3×10 mL) and thecombined EtOAc layer was dried (Na₂SO₄) and concentrated. The crudeproduct was dissolved in DCM and chromatographed through a Redi-Sep®pre-packed silica gel column (40 g), eluting with a gradient of 0% to 4%of MeOH in CH₂Cl₂, to provideN-(2-acetamidopyrimidin-5-yl)-6-chloro-3-(3-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxamideas an off-white solid. MS (ESI, pos. ion) m/z: 491 (M+1).

The following compounds, Examples 3-30 were made using a proceduresimilar to that described in Examples 1 and 2.

Ex. No. Name M + H 3 6-chloro-N-(pyrimidin-5-yl)-3-(3- 434(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxamide 46-chloro-3-(3-(morpholinomethyl)phenylamino)-N-(pyrimidin-5- 465.1yl)benzo[d]isoxazole-7-carboxamide 5 6-chloro-N-(pyrimidin-5-yl)-3-(4-434 (trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxamide 66-chloro-3-(3,3-dimethylindolin-6-ylamino)-N-(pyrimidin-5- 435.1yl)benzo[d]isoxazole-7-carboxamide 73-(3-tert-butylphenylamino)-6-chloro-N-(pyrimidin-5- 422.1yl)benzo[d]isoxazole-7-carboxamide 83-(4-tert-butylphenylamino)-6-chloro-N-(pyrimidin-5- 422.1yl)benzo[d]isoxazole-7-carboxamide 96-chloro-3-(3-cyanophenylamino)-N-(pyrimidin-5- 391.1yl)benzo[d]isoxazole-7-carboxamide 106-chloro-3-(4-fluoro-3-(trifluoromethyl)phenylamino)-N- 452.0(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide 116-chloro-3-(2,3-dichlorophenylamino)-N-(pyrimidin-5- 434.0yl)benzo[d]isoxazole-7-carboxamide 126-chloro-3-(3-fluoro-5-(trifluoromethyl)phenylamino)-N- 452.0(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide 136-chloro-3-(4-cyanophenylamino)-N-(pyrimidin-5- 391.1yl)benzo[d]isoxazole-7-carboxamide 143-(p-phenyl)-6-chloro-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide442.1 15 6-chloro-N-(pyrimidin-5-yl)-3-(4- 450.0(trifluoromethoxy)phenylamino)benzo[d]isoxazole-7-carboxamide 163-(3-(trifluoromethyl)benzylamino)-6-chloro-N-(pyrimidin-5- 448.1yl)benzo[d]isoxazole-7-carboxamide 176-chloro-3-(4-propylphenylamino)-N-(pyrimidin-5- 408.1yl)benzo[d]isoxazole-7-carboxamide 183-(4-butylphenylamino)-6-chloro-N-(pyrimidin-5- 422.1yl)benzo[d]isoxazole-7-carboxamide 196-chloro-3-(4-pentylphenylamino)-N-(pyrimidin-5- 436.1yl)benzo[d]isoxazole-7-carboxamide 20 6-chloro-N-(pyrimidin-5-yl)-3-(3-450.0 (trifluoromethoxy)phenylamino)benzo[d]isoxazole-7-carboxamide 216-chloro-3-(4-isopropylphenylamino)-N-(pyrimidin-5- 408.1yl)benzo[d]isoxazole-7-carboxamide 223-(4-sec-butylphenylamino)-6-chloro-N-(pyrimidin-5- 422.1yl)benzo[d]isoxazole-7-carboxamide 23N-(2-amino-5-pyrimidinyl)-6-chloro-3-((3- 449(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide 24N-(6-amino-3-pyridinyl)-6-chloro-3-((3- 448(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide 256-chloro-N-3-pyridinyl-3-((3-(trifluoromethyl)phenyl)amino)-1,2- 433benzisoxazole-7-carboxamide 26N-(2-(acetylamino)-5-pyrimidinyl)-6-chloro-3-((3- 491.1(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide 276-chloro-N-(6-chloro-3-pyridinyl)-3-((3- 467.1(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide 286-chloro-N-(2-chloro-5-pyrimidinyl)-3-((3- 468(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide 296-chloro-N-(6-(4-methyl-1-piperazinyl)-3-pyridinyl)-3-((3- 531.2(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide 306-chloro-N-(6-(4-morpholinyl)-3-pyridinyl)-3-((3- 518.1(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide

The following exemplary compounds will assist in the understanding thepresent invention, by further exemplifying the scope of the compounds ofFormulas I and II.

Ex. No. R1 R2 R5 31 1-piperidinyl Methyl or 2-CH₃-phenyl chloro 32cyclohexyl-N— Methyl or 4-CF₃-phenyl chloro 33 morpholine-(CH₂)₂—N—Methyl or 3-CF₃-phenyl chloro 34 (CH₃)₂N—(CH₂)₂—N— Methyl or6-CH₃-phenyl chloro 35 (C₂H₅)₂N—(CH₂)₂—N— Methyl or 2-OCH₃-phenyl chloro36 3-OH-1-pyrrolidinyl Methyl or 4-OCH₃-phenyl chloro 373-amido-1-pyrrolidinyl Methyl or pyridine chloro 384-amido-1-piperidinyl Methyl or indole chloro 39 3-amido-1-piperidinyl Hindoline 40 4N-CH₃-1-piperizinyl Methyl or benzofuran chloro 413-thiophene Methyl or 2-F-phenyl chloro 42 1-piperazinyl Methyl or4-F-phenyl chloro 43 1-piperidinyl Methyl or dihydrobenzofuran chloro 44cyclohexyl-N— Methyl or cyclohexyl-(CH₂)₂— chloro 453-amido-1-piperidinyl Methyl or cyclopropyl-(CH₂)₂— chloro 464-amido-1-piperidinyl Methyl or 3-thiophene chloro 47 1-morpholinylMethyl or 2-pyridine chloro 48 1-piperidinyl Methyl or 1-morpholinylchloro 49 cyclohexyl-N— Methyl or 1-piperazinyl chloro 50morpholine-(CH₂)₂—N— Methyl or 3-CF₃-phenyl chloro 51 pyrimidinyl Methylor 6-CH₃-phenyl chloro 52 pyridinyl Methyl or 2-OCH₃-phenyl chloro

All process steps described herein can be carried out under knownreaction conditions, preferably under those specifically mentioned, inthe absence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralizing agents, for example ion exchangers, typically cationexchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from about −100° C. to about 190° C.,preferably from about −80° C. to about 150° C., for example at about −80to about 60° C., at RT, at about −20 to about 40° C. or at the boilingpoint of the solvent used, under atmospheric pressure or in a closedvessel, where appropriate under pressure, and/or in an inert atmosphere,for example, under argon or nitrogen.

Salts may be present in all starting compounds and transients, if thesecontain salt-forming groups. Salts may also be present during thereaction of such compounds, provided the reaction is not therebydisturbed.

The solvents from which those can be selected which are suitable for thereaction in question include, for example, water, esters, typicallylower alkyl-lower alkanoates, e.g EtOAc, ethers, typically aliphaticethers, e.g. Et₂O, or cyclic ethers, e.g. THF, liquid aromatichydrocarbons, typically benzene or toluene, alcohols, typically MeOH,EtOH, IPA or 1-propanol, nitrites, typically AcCN, halogenatedhydrocarbons, typically CH₂Cl₂, acid amides, typically DMF, bases,typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids,typically lower alkanecarboxylic acids, e.g. HOAc, carboxylic acidanhydrides, typically lower alkane acid anhydrides, e.g. aceticanhydride, cyclic, linear, or branched hydrocarbons, typicallycyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g.aqueous solutions, unless otherwise stated in the description of theprocess.

The invention relates also to those forms of the process in which onestarts from a compound obtainable at any stage as a transient speciesand carries out the missing steps, or breaks off the process at anystage, or forms a starting material under the reaction conditions, oruses said starting material in the form of a reactive derivative orsalt, or produces a compound obtainable by means of the processaccording to the invention and processes the said compound in situ. Inthe preferred embodiment, one starts from those starting materials whichlead to the compounds described above as preferred.

The compounds of formula I or II, including their salts, are alsoobtainable in the form of hydrates, or their crystals can include forexample the solvent used for crystallization (present as solvates).

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention. Inone embodiment, such starting materials are used and reaction conditionsso selected as to enable the preferred compounds to be obtained.Starting materials of the invention, are known, are commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. In the preparation of starting materials,existing functional groups which do not participate in the reactionshould, if necessary, be protected. Preferred protecting groups, theirintroduction and their removal are described above or in the examples.All remaining starting materials are known, capable of being preparedaccording to known processes, or commercially obtainable; in particular,they can be prepared using processes as described in the examples.

The examples above serve to illustrate various embodiments of theinvention. The tables also contain the method by which these exampleswere prepared, with respect to the various schemes and examplespresented above. The schematic illustrations, detailed description ofthe methods, preparation of compounds of Formulas I or II, and compoundsdescribed above fall within the scope, and serve to exemplify the scopeof compounds contemplated in the invention. These detailed methoddescriptions are presented for illustrative purposes only and are notintended as a restriction on the scope of the present invention.

Biological Assays

The following assays can be employed to determine the degree of activityof a compound as a c-kit protein kinase modulator. Compounds describedherein have been tested in one or more of these assays, and have shownactivity. Representative compounds of the invention were tested andfound to exhibit IC₅₀ values of at least <10 μM in any one of thedescribed assays, thereby demonstrating and confirming the utility ofthe compounds of the invention as c-kit kinase inhibitors and in theprophylaxis and treatment of c-kit kinase activity-related disorders.

C-kit-Homogeneous Time Resolved Fluorescent (HTRF) Kinase Assay:

The purpose of this assay is to measure the inhibition of c-kit enzymeactivity (autophosphorylation and phosphorylation of substrate) by smallmolecule test compounds. The c-kit HTRF assay begins withc-kit-catalyzed phosphorylation of biotinylated peptide Her-2(N-GGMEDIYFEFMGGKKK-C) in the presence of ATP. The c-kit enzyme reactionis comprised of 1 μL of compound in 100% DMSO, 15 μL of 2× substrate mix(50 μM ATP and 2 μM biotinylated Her-2) and 15 μL of 2× c-kit (6.25 μM)(catalytic domain, N-terminal GST tagged, unphosphorylated) in 4 mM DTTall diluted in enzyme buffer (25 mM HEPES pH 7.5, 12.5 mM NaCl, 50 mMMgCl, 0.05% BSA). The reaction incubates for 90 min at RT. 160Microliters of detection mixture containing 0.47 μg/mL steptavidinallophycocyanin and 29.7 pM europylated anti-phosphotyrosine Ab (PT66,Perkin Elmer) in HTRF buffer (100 mM Hepes pH 7.5, 100 mM NaCl, 0.1%BSA, 0.05% Tween 20) is then added to stop the reaction, by diluting outthe enzyme as well as to enable quantitation of phosphorylated Her-2.After 3 h at RT, the detection reaction is read in a Packard Discovery™(model BD1000) plate reader. The wells are excited with coherent 320 nMlight and the ratio of delayed (50 ms post excitation) emissions at 620nM (native europium fluorescence) and 665 nm (europium fluorescencetransferred to allophycocyanin—an index of substrate phosphorylation) isdetermined. The proportion of substrate phosphorylated in the kinasereaction in the presence of compound compared with that phosphorylatedin the presence of DMSO vehicle alone (HI control) is calculated usingthe formula: % control (POC)=(cpd−average LO)/(average HI—averageLO)*100. Data (consisting of POC and inhibitor concentration in μM) isfitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)^D))), where A isthe minimum y (POC) value, B is the maximum y (POC), C is the x(compound concentration) at the point of inflection and D is the slopefactor) using a Levenburg-Marquardt non-linear regression algorithm.

Of the compounds tested, exemplary compounds 1-30 exhibited an averageIC₅₀ value of 10 uM or less in a human HTRF assay, for the inhibition ofthe c-kit kinase enzyme. Of the compounds tested, exemplary compounds1-15 and 17-27 exhibited an average IC₅₀ value of 200 nM or less in ahuman HTRF assay, for the inhibition of the c-kit kinase enzyme. Of thecompounds tested, exemplary compounds 1-3, 5-12, 15, 17-18 and 20-27exhibited an average IC₅₀ value of 100 nM or less in a human HTRF assay,for the inhibition of the c-kit kinase enzyme. Of the compounds tested,exemplary compounds 1-3, 5-8, 10, 12, 15, 17 and 20-26 exhibited anaverage IC₅₀ value of 20 nM or less in a human HTRF assay, for theinhibition of the c-kit kinase enzyme.

MO7e phosphorylated-cKIT (Tyr721) Electrochemiluminescent Immunoassay:

The purpose of this assay is to test the potency of small moleculecompounds on SCF-stimulated c-kit receptor phosphorylation of tyrosine721 (Tyr721) in MO7e cells. Activation of c-kit upon binding with it'sligand, stem cell factor (SCF), leads to dimerization/oligomerizationand autophosphorylation. Activation of c-kit results in the recruitmentand tyrosine phosphorylation of downstream SH2-containing signalingcomponents—such as the p85 subunit of PI3 kinase (Sattler, M. et al.(1997) J. Biol. Chem. 272, 10248-10253). C-kit phosphorylated at Tyr721binds to the p85 subunit of PI3 kinase (Blume-Jensen, P et al. (2000)Nature Genet. 24, 157-162). MO7e cells are a human megakaryoblasticfactor dependent leukemia cell line (carrying wild type c-kit receptor).Cells are maintained in growth media (IMDM, 10% HI-FBS, 1×PGS, 5 ng/mLGM-CSF). To measure SCF-induced c-kit phosphorylation, cells are washedand re-suspended to 3.3E5c/mL in assay media (RPMI 1640/4% HI-FBS,1×PGS) and plated at 30 uL/well for 10000 c/well. Small moleculecompounds are diluted in 100% DMSO. Cells are pre-incubated with 0.5-2μL compound for 1 h at RT. 10 Microliters of 4×SCF (100 ng/mL) in RTassay media is then added. After 30 min incubation at RT, the cells arelysed with the addition of 20 μL of ice cold 3× lysis buffer (20 mMTris-Cl, 1 mM EDTA, 150 mM NaCl, 1% NP-40, 2 mM NaF, 20 mM

-glycerophosphate, 1 mM Na₃VO₄ and 1 Complete Proteinase inhibitortablet/50 mL 1× lysis buffer (Roche Cat # 1697498, in stock room)). 25Microliters of lysate is transferred to blocked MSD plates (blocked with5% BSA in Tris-buffered saline, 0.01% Tween (TBS-T) for 1 h withshaking, then washed 3× with TBS-T) coated with anti-c-kit antibody(Labvision MS-289). After the plates are incubated with shaking for 1 hat RT, 25 μL of 10 nM ruthenylated detection antibody (Zymed 34-9400) isadded and the plate is incubated again with shaking for 1 h at RT. Theplates are then washed 3× with TBS-T, 150 μL of MSD Read Buffer T isadded, and the electrochemiluminescence (ECL) reaction is read on theSector Imager™ 6000. A low voltage is applied to the ruthenylatedphos-c-kit (Tyr721) immune complexes, which in the presence of TPA (theactive component in the ECL reaction buffer, Read Buffer T), results ina cyclical redox reaction generating light at 620 nm. The amount ofphosphorylated c-kit (Tyr721) in the presence of compounds compared withthat in the presence of vehicle alone (HI control) is calculated usingthe formula: % control (POC)=(cpd−average LO)/(averageHI−averageLO)*100. Data (consisting of POC and inhibitor concentrationin μM) is fitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)^D))),where A is the minimum y (POC) value, B is the maximum y (POC), C is thex (cpd concentration) at the point of inflection and D is the slopefactor) using a Levenburg-Marquardt non-linear regression algorithm.

SCF and GM-CSF Stimulated UT7 Proliferation/Survival Assay:

The purpose of this assay is to test the generalanti-proliferative/cytotoxic effect of small molecule compounds on SCFor GM-CSF-stimulated UT-7 cells. Preventing SCF stimulatedproliferation/survival is consistent with an on-mechanism effect whereasinhibition of GM-CSF driven proliferation/survival is indicative ofoff-target effects. UT-7 is a factor dependent human megakaryoblasticleukemia cell line that can be grown in either IL-3, GM-CSF, EPO or SCF(these cells have been confirmed to carry wild type c-kit receptor).Cells are maintained in growth media (IMDM, 10% HI-FBS, 1×PGS, 1 ng/mLGM-CSF). To measure SCF or GM-CSF-induced proliferation, cells arewashed and re-suspended to 5e4c/mL in assay media (RPMI 1640/4% HI-FBS,1×PGS) and plated at 50 uL/well for 2500c/well. Small molecule compoundsare first diluted in 100% DMSO, then diluted 1:4 in RT assay media. 5Microliters of 11×SCF (55 ng/mL) or 11×GM-CSF (11 ng/mL) in assay mediaplus 1 μL of diluted drug are added to the cell plates. The treatedcells are incubated in a 37° C. humidified incubator with 5% CO₂ for 3days. The amount of ATP is then measured as a surrogate marker for cellviability. This is accomplished by adding 50 μL of Perkin Elmer ATP 1step reagent (as per instructed in the reagent manual, Cat. No.6016739), incubating at RT for 15 min and reading the luminescence witha Perkin Elmer Topcount NXT™HTS (model c384) plate reader. The amount ofSCF or GM-CSF stimulated viable cells in the presence of compoundcompared with in the presence of vehicle alone (HI control) iscalculated using the formula: % control (POC)=(cpd−average LO)/(averageHI−average LO)*100. Data (consisting of POC and inhibitor concentrationin μM) is fitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)^D))),where A is the minimum y (POC) value, B is the maximum y (POC), C is thex (cpd concentration) at the point of inflection and D is the slopefactor) using a Levenburg-Marquardt non-linear regression algorithm.

Of the compounds tested, exemplary compounds 1-3, 5-12, 15 and 17-28exhibited; an average IC₅₀ value of 10 uM or less in the SCF and GM-CSFstimulated UT7 proliferation/survival assay. Of the compounds tested,exemplary compounds 1-3, 5-12, 15 and 17-28 exhibited an average IC₅₀value of 200 nM or less in the SCF and GM-CSF stimulated UT7proliferation/survival assay. Of the compounds tested, exemplarycompounds 1-3, 5-12, 15 and 17-28 exhibited an average IC₅₀ value of 100nM or less in the SCF and GM-CSF stimulated UT7 proliferation/survivalassay. Of the compounds tested, exemplary compounds 1-3, 5, 7-8, 10-12,15, 17, 18, and 20-28 exhibited an average IC₅₀ value of 20 nM or lessin the SCF and GM-CSF stimulated UT7 proliferation/survival assay.

Formulation and Modes of Administration/Methods of use

For the treatment of C-kit mediated diseases including those listedherein, the compounds of the present invention may be administered byseveral different modes, including without limitation, oral, parental,by spray inhalation, rectal, or topical, as discussed herein. The termparenteral as used herein, includes subcutaneous, intravenous,intramuscular, intrasternal, infusion techniques or intraperitonealadministration.

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention (or apharmaceutical salt, derivative or prodrug thereof), or a pharmaceuticalcomposition medicament comprising said compound, to a subject (i.e., toan animal, preferably a mammal, most preferably a human) believed to bein need of preventative treatment. Diseases or disorders which may betreated include, without limitation, allergies, mast cell related tumorsand other c-kit mediated conditions. Treatment also encompassesadministration of the compound, or a pharmaceutical compositioncomprising the compound, to subjects not having been diagnosed as havinga need thereof, i.e., prophylactic administration to the subject.Generally, the subject is initially diagnosed by a licensed physicianand/or authorized medical practitioner, and a regimen for prophylacticand/or therapeutic treatment via administration of the compound(s) orcompositions of the invention is suggested, recommended or prescribed.

“Treating” or “treatment of” within the context of the instantinvention, means an alleviation, in whole or in part, of symptomsassociated with a disorder or disease, or halt of further progression orworsening of those symptoms, or prevention or prophylaxis of the diseaseor disorder.

Similarly, as used herein, an “effective amount” or “therapeuticallyeffective amount” of a compound of the invention refers to an amount ofthe compound, or pharmaceutical composition, that alleviates, in wholeor in part, symptoms associated with a disorder or disease, or halts offurther progression or worsening of those symptoms, or prevents orprovides prophylaxis for the disease or disorder. For example, withinthe context of treating patients in need of an inhibitor of C-kit,successful treatment may include a reduction in mast cell mediatedtumor; an alleviation of symptoms related to a fibrotic condition; or ahalting in the progression of an allergic response.

While it may be possible to administer a compound of the inventionalone, in the methods described, the compound administered is generallypresent as an active ingredient in a desired dosage unit formulation,such as pharmaceutically acceptable composition (also referred to as“medicament” herein) containing conventional pharmaceutically acceptablecarriers. Thus, in another embodiment of the invention, there isprovided a pharmaceutical composition comprising a compound of thisinvention in combination with a pharmaceutically acceptable carrier.Acceptable pharmaceutical carriers generally include diluents,excipients, adjuvants and the like as described herein.

A pharmaceutical composition of the invention may comprise an effectiveamount of a compound of the invention or an effective dosage amount (orunit dosage amount) of a compound of the invention. An effective dosageamount of a compound of the invention includes an amount less than,equal to, or greater than an effective amount of the compound. Forexample, a pharmaceutical composition in which two or more unit dosages,such as in tablets, capsules and the like, are required to administer aneffective amount of the compound, or alternatively, a multi-dosepharmaceutical composition, such as powders, liquids and the like, inwhich an effective amount of the compound may be administered byadministering a portion of the composition.

The pharmaceutical compositions may generally be prepared by mixing oneor more compounds of Formula I or II including stereoisomersortautomers, solvates, pharmaceutically acceptable salts, derivatives orprodrugs thereof, with pharmaceutically acceptable carriers, excipients,binders, adjuvants, diluents and the like, to form a desiredadministrable formulation to treat or ameliorate a variety of disordersrelated to the activity of C-kit, particularly autoimmune disease.

Pharmaceutical compositions can be manufactured by methods well known inthe art such as conventional granulating, mixing, dissolving,encapsulating, lyophilizing, emulsifying or levigating processes, amongothers. The compositions can be in the form of, for example, granules,powders, tablets, capsules, syrup, suppositories, injections, emulsions,elixirs, suspensions or solutions. The instant compositions can beformulated for various routes of administration, for example, by oraladministration, by transmucosal administration, by rectaladministration, or subcutaneous administration as well as intrathecal,intravenous, intramuscular, intraperitoneal, intranasal, intraocular orintraventricular injection. The compound or compounds of the instantinvention can also be administered in a local rather than a systemicfashion, such as injection as a sustained release formulation.

Besides those representative dosage forms described herein,pharmaceutically acceptable excipients and carriers are generally knownto those skilled in the art and are thus included in the instantinvention. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (2000);and “Pharmaceutics The Science of Dosage Form Design, 2^(nd) Ed.(Aulton, ed.) Churchill Livingstone (2002). The following dosage formsare given by way of example and should not be construed as limiting theinvention.

For oral, buccal, and sublingual administration, powders, suspensions,granules, tablets, pills, capsules, gelcaps, and caplets are acceptableas solid dosage forms. These can be prepared, for example, by mixing oneor more compounds of the instant invention, or stereoisomers, solvates,prodrugs, pharmaceutically acceptable salts or tautomers thereof, withat least one additive or excipient such as a starch or other additiveand tableted, encapsulated or made into other desirable forms forconventional administration. Suitable additives or excipients aresucrose, lactose, cellulose sugar, mannitol, maltitol, dextran,sorbitol, starch, agar, alginates, chitins, chitosans, pectins,tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,synthetic or semi-synthetic polymers or glycerides, methyl cellulose,hydroxypropylmethyl-cellulose, and/or polyvinylpyrrolidone. Optionally,oral dosage forms can contain other ingredients to aid inadministration, such as an inactive diluent, or lubricants such asmagnesium stearate, or preservatives such as paraben or sorbic acid, oranti-oxidants such as ascorbic acid, tocopherol or cysteine, adisintegrating agent, binders, thickeners, buffers, sweeteners,flavoring agents or perfuming agents. Additionally, dyestuffs orpigments may be added for identification. Tablets and pills may befurther treated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions,slurries and solutions, which may contain an inactive diluent, such aswater. Pharmaceutical formulations may be prepared as liquid suspensionsor solutions using a sterile liquid, such as, but not limited to, anoil, water, an alcohol, and combinations of these. Pharmaceuticallysuitable surfactants, suspending agents, emulsifying agents, and thelike may be added for oral or parenteral administration.

For nasal administration, the pharmaceutical formulations may be a sprayor aerosol containing an appropriate solvent and optionally othercompounds such as, but not limited to, stabilizers, antimicrobialagents, antioxidants, pH modifiers, surfactants, bioavailabilitymodifiers and combinations of these. A propellant for an aerosolformulation may include compressed air, nitrogen, carbon dioxide, or ahydrocarbon based low boiling solvent. The compound or compounds of theinstant invention are conveniently delivered in the form of an aerosolspray presentation from a nebulizer or the like.

Injectable dosage forms for parenteral administration generally includeaqueous suspensions or oil suspensions, which may be prepared using asuitable dispersant or wetting agent and a suspending agent. Injectableforms may be in solution phase or a powder suitable for reconstitutionas a solution. Both are prepared with a solvent or diluent. Acceptablesolvents or vehicles include sterilized water, Ringer's solution, or anisotonic aqueous saline solution. Alternatively, sterile oils may beemployed as solvents or suspending agents. Typically, the oil or fattyacid is non-volatile, including natural or synthetic oils, fatty acids,mono-, di- or tri-glycerides. For injection, the formulations mayoptionally contain stabilizers, pH modifiers, surfactants,bioavailability modifiers and combinations of these. The compounds maybe formulated for parenteral administration by injection such as bybolus injection or continuous infusion. A unit dosage form for injectionmay be in ampoules or in multi-dose containers.

For rectal administration, the pharmaceutical formulations may be in theform of a suppository, an ointment, an enema, a tablet or a cream forrelease of compound in the intestines, sigmoid flexure and/or rectum.Rectal suppositories are prepared by mixing one or more compounds of theinstant invention, or pharmaceutically acceptable salts or tautomers ofthe compound, with acceptable vehicles, for example, cocoa butter orpolyethylene glycol, which is solid phase at room temperature but liquidphase at those temperatures suitable to release a drug inside the body,such as in the rectum. Various other agents and additives may be used inthe preparation of suppositories as is well known to those of skill inthe art.

The formulations of the invention may be designed to be short-acting,fast-releasing, long-acting, and sustained-releasing as described below.Thus, the pharmaceutical formulations may also be formulated forcontrolled release or for slow release. The instant compositions mayalso comprise, for example, micelles or liposomes, or some otherencapsulated form, or may be administered in an extended release form toprovide a prolonged storage and/or delivery effect. Therefore, thepharmaceutical formulations may be compressed into pellets or cylindersand implanted intramuscularly or subcutaneously as depot injections oras implants such as stents. Such implants may employ known inertmaterials such as silicones and biodegradable polymers.

Specific dosages may be adjusted depending on conditions of disease, theage, body weight, general health conditions, sex, and diet of thesubject, dose intervals, administration routes, excretion rate, andcombinations of drugs. Any of the above dosage forms containingeffective amounts are well within the bounds of routine experimentationand therefore, well within the scope of the instant invention.

A therapeutically effective dosage amount or dose may vary dependingupon the route of administration and dosage form. Typically, thecompound or compounds of the instant invention are selected to provide aformulation that exhibits a high therapeutic index. The therapeuticindex is the dose ratio between toxic and therapeutic effects which canbe expressed as the ratio between LD₅₀ and ED₅₀. The LD₅₀ is the doselethal to 50% of the population and the ED₅₀ is the dose therapeuticallyeffective in 50% of the population. The LD₅₀ and ED₅₀ are determined bystandard pharmaceutical procedures in animal cell cultures orexperimental animals.

The dosage regimen for treating C-kit mediated diseases with thecompounds of this invention and/or compositions of this invention isbased on a variety of factors, including the type of disease, the age,weight, sex, medical condition of the patient, the severity of thecondition, the route of administration, and the particular compoundemployed. Thus, the dosage regimen may vary widely, but can bedetermined routinely using standard methods. Dosage levels of the orderfrom about 0.01 mg to 30 mg per kilogram of body weight per day,preferably from about 0.1 mg to 10 mg/kg, more preferably from about0.25 mg to 1 mg/kg are useful for all methods of use disclosed herein.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose. A suitable topicaldose of active ingredient of a compound of the invention is 0.1 mg to150 mg administered one to four, preferably one or two times daily. Fortopical administration, the active ingredient may comprise from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of the formulation, althoughit may comprise as much as 10% w/w, but preferably not more than 5% w/w,and more preferably from 0.1% to 1% of the formulation.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. The pharmaceutically active compoundsof this invention can be processed in accordance with conventionalmethods of pharmacy to produce medicinal agents for administration topatients, including humans and other mammals.

While the compounds of the present invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or with one or more otheragents. When administered as a combination, the therapeutic agents canbe formulated and given to the subject as a single composition or thecombination of therapeutic agents can be formulated and given to thesubject as separate compositions that are given at the same time ordifferent times.

Treatment may also include administering the pharmaceutical formulationsof the present invention in combination with other therapies. Forexample, the compounds and pharmaceutical formulations of the presentinvention may be administered before, during, or after surgicalprocedure and/or radiation therapy. Alternatively, the compounds of theinvention can also be administered in conjunction with otheranti-proliferative agents including those used in antisense and genetherapy.

The methods and compositions of the present invention may comprise acombination with another kinase inhibitor. Although the presentinvention is not limited to any particular kinase, kinase inhibitorscontemplated for use include, without limitation, tyrphostin AG490(2-cyano-3-(3,4-dihydroxyphenyl)-N-(benzyl)-2-propenamide), Iressa(ZD1839; Astra Zeneca); Gleevec (STI-571 or imatinib mesylate;Novartis); SU5416 (Pharmacia Corp./Sugen); and Tarceva (OSI-774;Roche/Genentech/OSI Pharmaceuticals).

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

1. A compound of Formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Ais N or CH; Y is N or CR³; each R^(1 ′), independently, is NR⁹R⁹, OR⁹,R⁷ or R⁹ and n is 0-3, wherein R⁷ is H, C₁₋₈-alkyl or C₃₋₈-cycloalkyl,each of the C₁₋₈-alkyl and C₃₋₈-cycloalkyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with 1-3substituents of NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹,C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁹), S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹ or R⁹; each R⁹,independently, of NR⁹R⁹ is H, acetyl or C₁₋₈alkyl; and R⁹ of OR⁹ is H,haloalkyl, acetyl or C₁₋₈alkyl; R² is H, halo, haloalkyl, NO₂,C₁₋₈alkyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH, —S—C₁₋₈alkyl, NH₂,—NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or —C(O)—C₁₋₈alkyl; R³, at eachoccurrence, is H, halo, haloalkyl, NO₂, C₁₋₈alkyl, CN, OH, —O—C₁₋₈alkyl,—O-haloalkyl, SH, —S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or—C(O)—C₁₋₈alkyl; R⁴ is H or C₁₋₈alkyl; R⁵ is a phenyl, naphthyl,pyridyl, pyrimidinyl, triazinyl, pyridazinyl, thiophenyl, furyl,tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, phthalazinyl, thieno-pyrazolyl,imidazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl,isoxazolyl, isothiazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl,indolyl, azaindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, pyrrolidinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl, cyclopropyl, cyclobutyl, azetidinyl,cyclopentyl or cyclohexyl, each of which is optionally substitutedindependently with 1-5 substituents of R⁹; R⁶, at each occurrence, is Hor C₁₋₈alkyl; and each R⁹, independently, is H, halo, haloalkyl, CN, OH,NO₂, NH₂, acetyl, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₃₋₈-cycloalkyl, C₁₋₈alkylamino-, C₁₋₈dialkylamino-, C₁₋₈-alkoxyl,C₁₋₈-thioalkoxyl or a saturated 6-membered monocyclic ring system formedof carbon atoms including 1-2 heteroatoms, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₈alkyl, C₂₋₈-alkenyl,C₂₋₈-alkynyl, C₃₋₈-cycloalkyl, C₁₋₈alkylamino-, C₁₋₈dialkylamino-,C₁₋₈-alkoxyl, C₁₋₈-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-3 substituents ofC₁₋₄-alkyl, methyl.
 2. The compound of claim 1 wherein Y is N.
 3. Thecompound of claim 1 wherein R² is H, F, Br, Cl, I, CF₃, CH₂CF₃, NO₂,C₁₋₈alkyl, CN, OH, —OCH₃, —OC₂H₅, —OCF₃, NH₂, —NH—C₁₋₆alkyl or—N—(C₁₋₈alkyl)₂.
 4. The compound of claim 1 wherein R⁵ is phenyl,naphthyl, 2-pyridyl, 2,6-pyrimidinyl, triazinyl, pyridazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, 2,5-imidazolyl, triazolyl, 2,5-thiazolyl,thiadiazolyl, 2,5-oxazolyl, oxadiazolyl, isoxazolyl, 2,5-isothiazolyl,benzoxazolyl, benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl,isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothiophenyl,benzimidazolyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl orcyclohexyl, each of which is optionally substituted independently with1-5 substituents of R⁹.
 5. The compound of claim 1 wherein X is O; R² isH, F, Br, Cl, I, CF₃, CH₂CF₃, NO₂, C₁₋₈alkyl, CN, OH, —OCH₃, —OC₂H₅,—OCF₃, NH₂, —NH—C₁₋₆alkyl or —N—(C₁₋₈alkyl)₂. R³ and R⁴, at eachoccurrence, is H or C₁₋₈alkyl; R⁵ is phenyl, naphthyl, pyridyl,pyrimidinyl, triazinyl, pyridazinyl, thiophenyl, furyl, tetrahydrofuryl,pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, phthalazinyl, thieno-pyrazolyl, imidazolyl, triazolyl,thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl,isothiazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, indolyl,azaindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl,benzimidazolyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl orcyclohexyl, each of which is optionally substituted independently with1-5 substituents of R⁹; and R⁶, at each occurrence, is H or C₁₋₈alkyl.6. The compound of claim 1 having a Formula II

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Ais N or CH; Y is N or CR³; each R^(1′), independently, is NR⁹R⁹, OR⁹, R⁷or R⁹ and n is 0-3, wherein R⁷ is H, C₁₋₈-alkyl or C₃₋₈-cycloalkyl, eachof the C₁₋₈-alkyl and C₃₋₈-cycloalkyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with 1-3substituents of NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹,C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁹), S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹ or R⁹; each R⁹,independently, of NR⁹R⁹ is H, acetyl or C₁₋₈alkyl; and R⁹ of OR⁹ is H,haloalkyl, acetyl or C₁₋₈alkyl, ; R² is H, halo, haloalkyl, NO₂,C₁₋₈alkyl, CN, OH, —O—C₁₋₈alkyl, —O—haloalkyl, SH, —S—C₁₋₈alkyl, NH₂,—NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or —C(O)—C₁₋₈alkyl; R³, at eachoccurrence, is H, halo, haloalkyl, NO₂, C₁₋₈alkyl, CN, OH, —O—C₁₋₈alkyl,—O-haloalkyl, SH, —S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or—C(O)—C₁₋₈alkyl; R⁴ is H or C₁₋₈alkyl; R⁵ is phenyl, naphthyl,2-pyridyl, 2,6-pyrimidinyl, triazinyl, pyridazinyl, thiophenyl, furyl,tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, phthalazinyl, thieno-pyrazolyl,2,5-imidazolyl, triazolyl, 2,5-thiazolyl, thiadiazolyl, 2,5-oxazolyl,oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl, benzothiazolyl,benzoxadiazolyl, indolyl, azaindolyl, isoindolyl, indazolyl,benzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted independently with 1-5 substituents of R⁹; R⁶, ateach occurrence, is H or C₁₋₈alkyl; and each R⁹, independently, is H,halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₈-alkyl, C₂₋₈-alkenyl,C₂₋₈-alkynyl, C₃₋₈-cycloalkyl, C₁₋₈alkylamino-, C₁₋₈-dialkylamino-,C₁₋₈-alkoxyl, C₁₋₈-thioalkoxyl or a saturated 6-membered monocyclic ringsystem formed of carbon atoms including 1-2 heteroatoms, saidheteroatoms selected from O, N, or S, wherein each of the C₁₋₈alkyl,C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl, C₁₋₈-alkylamino-,C₁₋₈-dialkylamino-, C₁₋₈-alkoxyl, C₁₋₈-thioalkoxyl and ring of said ringsystem is optionally substituted independently with 1-3 substituents ofC₁₋₈-alkyl.
 7. The compound of claim 6 wherein A is N; Y is N or CR³;R^(1′)is NR⁹R⁹, R⁷ or R⁹ and n is 0-3; R² is halo, haloalkyl, NO₂,C₁₋₈alkyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH, —S—C₁₋₈alkyl, NH₂,—NH—C₁₋₈alkyl or —N—(C₁₋₈alkyl)₂; R³, at each occurrence, is H; R⁴ is Hor C₁₋₈alkyl; and R⁶ is H or C₁₋₈alkyl.
 8. The compound of claim 1 or apharmaceutically acceptable salt thereof, selected from:6-chloro-N-(pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxamide;6-chloro-3-(4-ethylphenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;6-chloro-3-(3-(morpholinomethyl)phenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;6-chloro-N-(pyrimidin-5-yl)-3-(4-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxamide;6-chloro-3-(3,3-dimethylindolin-6-ylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;3-(3-tert-butylphenylamino)-6-chloro-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;3-(4-tert-butylphenylamino)-6-chloro-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;6-chloro-3-(3-cyanophenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;6-chloro-3-(4-fluoro-3-(trifluoromethyl)phenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;6-chloro-3-(2,3-dichlorophenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;6-chloro-3-(3-fluoro-5-(trifluoromethyl)phenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;6-chloro-3-(4-cyanophenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;3-(p-phenyl)-6-chloro-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;6-chloro-N-(pyrimidin-5-yl)-3-(4-(trifluoromethoxy)phenylamino)benzo[d]isoxazole-7-carboxamide;3-(3-(trifluoromethyl)benzylamino)-6-chloro-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;6-chloro-3-(4-propylphenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;3-(4-butylphenylamino)-6-chloro-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;6-chloro-3-(4-pentylphenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;6-chloro-N-(pyrimidin-5-yl)-3-(3-(trifluoromethoxy)phenylamino)benzo[d]isoxazole-7-carboxamide;6-chloro-3-(4-isopropylphenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;3-(4-sec-butylphenylamino)-6-chloro-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide;N-(2-amino-5-pyrimidinyl)-6-chloro-3-((3-(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide;N-(6-amino-3-pyridinyl)-6-chloro-3-((3-(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide;N-(6-(acetylamino)-3-pyridinyl)-6-chloro-3-((3-(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide;6-chloro-N-3-pyridinyl-3-((3-(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide;N-(2-(acetylamino)-5-pyrimidinyl)-6-chloro-3-((3-(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide;6-chloro-N-(6-chloro-3-pyridinyl)-3-((3-(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide;6-chloro-N-(2-chloro-5-pyrimidinyl)-3-((3-(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide;and6-chloro-N-(6-(4-methyl-1-piperazinyl)-3-pyridinyl)-3-((3-(trifluoromethyl)phenyl)amino)-1,2-benzisoxazole-7-carboxamide.9. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound according to claim
 1. 10. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound according to claim
 6. 11. A method of making a compoundaccording to claim 1, the method comprising the step of reacting acompound 8 having the general formula

wherein R², R³, R⁵ and Y are as defined in claim 1 with a compoundhaving a general formula NHR¹R⁶, wherein R¹ and R⁶ are defined in claim1, in the presence of a carboxylic acid activating agent, to make acompound of claim 1.